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1.
J Am Coll Cardiol ; 75(6): 575-577, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32057370
3.
JAMA ; 322(18): 1780-1788, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714986

RESUMO

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade
4.
J Lipid Res ; 60(11): 1953-1958, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31519763

RESUMO

Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5' untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5'UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.

5.
JAMA Ophthalmol ; 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31536098

RESUMO

Importance: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive bile acid synthesis disorder caused by mutations in CYP27A1, the gene encoding sterol 27-hydroxylase, which results in elevated levels of plasma cholestanol and urinary bile alcohols. Clinical symptoms and signs may include early-onset chronic diarrhea, juvenile-onset bilateral cataracts, cholestatic jaundice, tendon xanthomas, and progressive neurological deterioration. Although initiation of treatment at a young age can prevent disease complications, diagnosis often occurs after the onset of permanent neurologic damage. Strategies are needed to facilitate early diagnosis. Objective: To evaluate the prevalence of CTX in a patient population diagnosed with early-onset idiopathic bilateral cataracts. Design, Setting, and Participants: This interim analysis of the Cerebrotendinous Xanthomatosis Prevalence Study was conducted in 26 active US sites from November 2015 to June 2017. The study included patients diagnosed as having idiopathic bilateral cataracts from ages 2 to 21 years. Potentially eligible study participants were identified through retrospective medical record review or on receiving care for cataracts at an active site. Data were analyzed from July 2017 to October 2018. Main Outcomes and Measures: Measurement of plasma cholestanol levels and optional urine bile alcohol screening were performed. A plasma cholestanol concentration of 0.4 mg/dL or greater or a positive urine bile alcohol result prompted CYP27A1 genetic testing to confirm the diagnosis of CTX. Results: Of 170 tested patients, 88 (51.8%) were male, and the median (range) age was 10 (2-49) years. A total of 3 patients (1.8%) had biochemical and genetic confirmation of newly diagnosed CTX (plasma cholestanol level greater than 1.0 mg/dL, positive urine bile alcohol result, and disease-causative mutations in CYP27A1). The mean (range) age at cataract diagnosis for patients with CTX was 12 (8-16) years. Reported symptoms included abnormal gait or balance (n = 3), learning disability (n = 2), cognitive decline (n = 2), seizures (n = 2), frequent bone fractures (n = 2), and chronic diarrhea (n = 1). Conclusions and Relevance: To date, 1.8% of patients in this study were diagnosed as having CTX, which is approximately 500-fold the currently estimated prevalence of CTX in the general population (3 to 5 per 100 000). These data suggest that juvenile-onset idiopathic bilateral cataracts may be useful as a screening marker for CTX and that ophthalmologists can play an important role in facilitating early identification of this condition.

6.
Atherosclerosis ; 289: 85-93, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31487564

RESUMO

BACKGROUND AND AIMS: There are limited data from the US on outcomes of patients in specialty care for familial hypercholesterolemia (FH). METHODS: CASCADE FH Registry data were analyzed to assess longitudinal changes in medication usage, in low density lipoprotein cholesterol (LDL-C) levels, and the rate of major adverse cardiovascular events (MACE (myocardial infarction, coronary revascularization, stroke or transient ischemic attack) in adults with FH followed in US specialty clinics. RESULTS: The cohort consisted of 1900 individuals (61% women, 87% Caucasian), with mean age of 56 ±â€¯15 years, 37% prevalence of ASCVD at enrollment, mean pretreatment LDL-C 249 ±â€¯68 mg/dl, mean enrollment LDL-C 145 mg/dl and 93% taking lipid lowering therapy. Over follow up of 20 ±â€¯11 months, lipid lowering therapy use increased (mean decrease in LDL-C of 32 mg/dl (p < 0.001)). Only 48% of participants achieved LDL-C < 100 mg/dl and 22% achieved LDL-C < 70 mg/dl; ASCVD at enrollment was associated with greater likelihood of goal achievement. MACE event rates were almost 6 times higher among patients with prior ASCVD compared to those without (4.6 vs 0.8/100 patient years). Also associated with incident MACE were markers of FH severity and conventional ASCVD risk factors. CONCLUSIONS: With care in FH specialized clinics, LDL-C decreased, but LDL-C persisted >100 mg/dl in 52% of patients. High ASCVD event rates suggest that adults with FH warrant designation as having an ASCVD risk equivalent. Earlier and more aggressive therapy of FH is needed to prevent ASCVD events.

7.
J Clin Lipidol ; 13(4): 511-521, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31500839

RESUMO

Until 1990, lipid clinics in the United States existed only in academic medical centers, generally in close relationship with laboratory-based research programs. The advent of statin therapy, the success of major clinical trials to prevent or stabilize atherosclerotic cardiovascular disease, and organizational efforts highlighted by regional Lipid Disorders Training Centers and the newly formed National Lipid Association boosted the formation of lipid clinics and preventive cardiology clinics in private and academic settings. This roundtable discussion with 4 experts examines multiple aspects of lipid clinic operations: obtaining referrals, adapting to either the academic or community setting, organizing a team of providers, incorporating diet and lifestyle counseling as well as medication, establishing the pharmacist role, and gaining financial stability. Some issues are as yet unsettled, including the subspecialty home of lipidology, if any, and the diagnostic and management boundaries of practical lipid clinics. Achieving official recognition as a subspecialty has taken some steps forward but remains a challenge. Opportunities for advocacy need to be seized.

8.
J Clin Lipidol ; 13(2): 231-245, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30928441

RESUMO

Solid organ transplantation (SOT) has revolutionized treatment of end-stage disease. Improvements in the SOT continuum of care have unmasked a significant burden of cardiovascular disease, manifesting as a leading cause of morbidity and mortality. Although several risk factors for development of post-transplant cardiovascular disease exist, dyslipidemia remains one of the most frequent and modifiable risks. An important contributor to dyslipidemia in SOT recipients is the off-target metabolic effects of immunosuppressive medications, which may alter lipoproteins and their metabolism. Dyslipidemia management is paramount as lipid-lowering therapy with statins has demonstrated reductions in graft vasculopathy, decreased rejection rates, and improved survival. Several nonstatin medication options are available, but data supporting their benefit in the SOT population are minimal, typically extrapolated from studies in the general population. Further compounding dyslipidemia management is the complex interplay of drug interactions between lipid-lowering and immunosuppressant medications, which can result in serious toxicity and/or therapeutic failure.

9.
Circ Res ; 124(1): 32-37, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30605414

RESUMO

PCSK9i (protein convertase subtilisin/kexin type 9 inhibitors) are set to revolutionize the treatment of hypercholesterolemia in the management of atherosclerotic risk, but numerous reports have detailed unprecedented barriers to access for these drugs. To overcome these challenges, our group created a model to facilitate provision of this new therapy for patients who qualify according to Food and Drug Administration criteria. This report details the real-world follow-up experience of PCSK9i use in a large patient cohort structured to ensure rigor in data collection, analysis, and interpretation. The 271 patients approved and actively followed in our PCSK9i clinic between July 2015 and August 2018 represent a 97% approval rate from insurance, with 28% of prescriptions requiring at least one appeal. Over 50% of patients were statin intolerant. On average, there was a median lapse of 15 days between initial visit and insurance approval. PCSK9i therapy was affordable for most patients, with an average monthly out-of-pocket expense of $58.05 (median $0). Only 2.3% of patients were unable to initiate or continue therapy because of cost. Reductions from baseline in LDL (low-density lipoprotein) cholesterol and Lp(a) (lipoprotein [a])were comparable to published reports with median reductions of 60% and 23% at 1 year, respectively. PCSK9i therapy was well-tolerated overall, though 9% of patients reported adverse events, and 5% of patients discontinued due mostly to musculoskeletal and flu-like symptoms. Our practice model demonstrates that PCSK9i therapy can be accessed easily and affordably for the majority of eligible patients, resulting in dramatic improvement in lipid profile results. Moreover, our registry data suggest that results from the prospective clinical trials of PCSK9i on LDL and Lp(a) reduction and on tolerability are applicable to a real-world cohort.


Assuntos
Anticolesterolemiantes/economia , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Custos de Medicamentos , Hipercolesterolemia/tratamento farmacológico , Lipídeos/sangue , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/economia , Inibidores de Serino Proteinase/uso terapêutico , Idoso , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/economia , Doenças Cardiovasculares/epidemiologia , Tomada de Decisão Clínica , Definição da Elegibilidade/economia , Feminino , Gastos em Saúde , Acesso aos Serviços de Saúde/economia , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/economia , Hipercolesterolemia/epidemiologia , Masculino , Assistência Médica/economia , Pessoa de Meia-Idade , Oregon , Pró-Proteína Convertase 9/metabolismo , Estudos Prospectivos , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
10.
Atherosclerosis ; 280: 109-117, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30500603

RESUMO

BACKGROUND AND AIMS: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular disease risk. Despite multiple LDL-C-lowering therapies, many HeFH patients do not reach LDL-C targets. Mipomersen, an antisense oligonucleotide against apolipoprotein B (apoB), might further lower LDL-C in HeFH patients. We assessed the efficacy and safety of two mipomersen dosing regimens in HeFH patients and explored whether thrice-weekly dosing improves the benefit-risk profile. METHODS: In this double-blind trial, HeFH patients (LDL-C >160 mg/dL) on maximal tolerated LDL-lowering therapy were randomized to mipomersen 200 mg once weekly (n = 104), mipomersen 70 mg thrice weekly (n = 102), or placebo in matching frequency (n = 103) for 60 weeks. Main outcomes were LDL-C, apoB, and lipoprotein(a) levels after 60 weeks of treatment. RESULTS: Mipomersen 200 mg once weekly and mipomersen 70 mg thrice weekly significantly lowered LDL-C compared with placebo by 21.0% and 18.8%, respectively, and apoB by 22.1% and 21.7% (all p < 0.001). Lipoprotein(a) was significantly lowered by 27.7% (p < 0.001) with thrice-weekly dosing. Injection-site reactions and flu-like symptoms led to discontinuation in 21.2% (200 mg), 17.6% (70 mg), and 5.8% (placebo) of participants. Alanine transaminase was elevated (≥3× upper limit of normal at least once) in 21.2%, 21.6%, and 1.0% of subjects, respectively. CONCLUSIONS: Mipomersen 200 mg once weekly and 70 mg thrice weekly are effective in lowering apoB-containing lipoproteins in HeFH patients. This is counterbalanced by limited tolerability and increased hepatic transaminase levels in about 21% of patients. The thrice-weekly dosing regimen was associated with lower frequency of flu-like symptoms, which might help avert discontinuation in some patients, but otherwise had no major benefits.

11.
JACC Cardiovasc Imaging ; 12(8 Pt 1): 1430-1440, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-29909101

RESUMO

OBJECTIVES: This study evaluated whether lipoprotein apheresis produces immediate changes in resting perfusion in subjects with severe hypercholesterolemia, and whether there is a difference in the response between peripheral and coronary microcirculations. BACKGROUND: Lipoprotein apheresis is used in patients with severe hypercholesterolemia to reduce plasma levels of low-density lipoprotein cholesterol. METHODS: Quantitative contrast-enhanced ultrasound perfusion imaging of the myocardium at rest and skeletal muscle at rest and during calibrated contractile exercise was performed before and immediately after lipoprotein apheresis in 8 subjects with severe hypercholesterolemia, 7 of whom had a diagnosis of familial hypercholesterolemia. Myocardial perfusion imaging was also performed in 14 normal control subjects. Changes in myocardial work and left ventricular function were assessed by echocardiography. Ex vivo ovine coronary and femoral artery ring tension assays were assessed in the presence of pre- and post-apheresis plasma. RESULTS: Apheresis acutely decreased low-density lipoprotein cholesterol (234.9 ± 103.2 mg/dl vs. 67.1 ± 49.5 mg/dl; p < 0.01) and oxidized phospholipid on apolipoprotein B-100 (60.2 ± 55.2 nmol/l vs. 47.0 ± 24.5 nmol/l; p = 0.01), and acutely increased resting myocardial perfusion (55.1 [95% confidence interval: 77.2 to 73.1] IU/s vs. 135 [95% confidence interval: 81.2 to 189.6] IU/s; p = 0.01), without changes in myocardial work. Myocardial longitudinal strain improved in those subjects with reduced pre-apheresis function. Skeletal muscle perfusion at rest and during contractile exercise was unchanged by apheresis. Acetylcholine-mediated dilation of ex vivo ovine coronary but not femoral arteries was impaired in pre-apheresis plasma and was completely reversed in post-apheresis plasma. CONCLUSIONS: Lipoprotein apheresis produces an immediate improvement in coronary microvascular function, which increases myocardial perfusion and normalizes endothelial-dependent vasodilation. These changes are not observed in the periphery. (Acute Microvascular Changes With LDL Apheresis; NCT02388633).

12.
Arterioscler Thromb Vasc Biol ; 39(2): e38-e81, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30580575

RESUMO

One in 4 Americans >40 years of age takes a statin to reduce the risk of myocardial infarction, ischemic stroke, and other complications of atherosclerotic disease. The most effective statins produce a mean reduction in low-density lipoprotein cholesterol of 55% to 60% at the maximum dosage, and 6 of the 7 marketed statins are available in generic form, which makes them affordable for most patients. Primarily using data from randomized controlled trials, supplemented with observational data where necessary, this scientific statement provides a comprehensive review of statin safety and tolerability. The review covers the general patient population, as well as demographic subgroups, including the elderly, children, pregnant women, East Asians, and patients with specific conditions such as chronic disease of the kidney and liver, human immunodeficiency viral infection, and organ transplants. The risk of statin-induced serious muscle injury, including rhabdomyolysis, is <0.1%, and the risk of serious hepatotoxicity is ≈0.001%. The risk of statin-induced newly diagnosed diabetes mellitus is ≈0.2% per year of treatment, depending on the underlying risk of diabetes mellitus in the population studied. In patients with cerebrovascular disease, statins possibly increase the risk of hemorrhagic stroke; however, they clearly produce a greater reduction in the risk of atherothrombotic stroke and thus total stroke, as well as other cardiovascular events. There is no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis. In US clinical practices, roughly 10% of patients stop taking a statin because of subjective complaints, most commonly muscle symptoms without raised creatine kinase. In contrast, in randomized clinical trials, the difference in the incidence of muscle symptoms without significantly raised creatinine kinase in statin-treated compared with placebo-treated participants is <1%, and it is even smaller (0.1%) for patients who discontinued treatment because of such muscle symptoms. This suggests that muscle symptoms are usually not caused by pharmacological effects of the statin. Restarting statin therapy in these patients can be challenging, but it is important, especially in patients at high risk of cardiovascular events, for whom prevention of these events is a priority. Overall, in patients for whom statin treatment is recommended by current guidelines, the benefits greatly outweigh the risks.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , American Heart Association , Hemorragia Cerebral/induzido quimicamente , Diabetes Mellitus/induzido quimicamente , Interações de Medicamentos , Humanos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Rabdomiólise/induzido quimicamente , Estados Unidos
13.
J Clin Lipidol ; 12(5): 1169-1178, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30017468

RESUMO

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare disorder due to defective sterol 27-hydroxylase causing a lack of chenodeoxycholic acid (CDCA) production and high plasma cholestanol levels. OBJECTIVES: Our objective was to review the diagnosis and treatment results in 43 CTX cases. METHODS: We conducted a careful review of the diagnosis, laboratory values, treatment, and clinical course in 43 CTX cases. RESULTS: The mean age at diagnosis was 32 years; the average follow-up was 8 years. Cases had the following conditions: 53% chronic diarrhea, 74% cognitive impairment, 70% premature cataracts, 77% tendon xanthomas, 81% neurologic disease, and 7% premature cardiovascular disease. The mean serum cholesterol concentration was 190 mg/dL; the mean plasma cholestanol level was 32 mg/L (normal <5.0 mg/L), which decreased to 6.0 mg/L (-81%) with CDCA therapy generally given as 250 mg orally 3 times daily. Of those tested on treatment, 63% achieved cholestanol levels of <5.0 mg/L; 91% had normal liver enzyme levels; none had significant liver problems after dose adjustment. Treatment improved symptoms in 57% at follow-up, but 20% with advanced disease continued to deteriorate. In the United States, CDCA has been approved for gallstone dissolution, but not for CTX despite long-term efficacy and safety data. CONCLUSIONS: Health care providers seeing young patients with tendon xanthomas and relatively normal cholesterol levels, especially those with cataracts and learning problems, should consider the diagnosis of CTX so they can receive treatment. CDCA should receive regulatory approval to facilitate therapy for the prevention of the complications of the disease.


Assuntos
Xantomatose Cerebrotendinosa/diagnóstico , Xantomatose Cerebrotendinosa/terapia , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
14.
Biochimie ; 153: 86-98, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29960034

RESUMO

Dihydroxyoxocholestenoic acids are intermediates in bile acid biosynthesis. Here, using liquid chromatography - mass spectrometry, we confirm the identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in cerebrospinal fluid (CSF) based on comparisons to authentic standards and of 7α,12α-dihydroxy-3-oxocholest-4-en-26-oic and 7α,x-dihydroxy-3-oxocholest-4-en-26-oic (where hydroxylation is likely on C-22 or C-23) based on exact mass measurement and multistage fragmentation. Surprisingly, patients suffering from the inborn error of metabolism cerebrotendinous xanthomatosis, where the enzyme CYP27A1, which normally introduces the (25 R)26-carboxylic acid group to the sterol side-chain, is defective still synthesise 7α,24-dihydroxy-3-oxocholest-4-en-26-oic acid and also both 25 R- and 25 S-epimers of 7α,12α-dihydroxy-3-oxocholest-4-en-26-oic acid. We speculate that the enzymes CYP46A1 and CYP3A4 may have C-26 carboxylase activity to generate these acids. In patients suffering from hereditary spastic paraplegia type 5 the CSF concentrations of the 7α,24- and 7α,25-dihydroxy acids are reduced, suggesting an involvement of CYP7B1 in their biosynthesis in brain.


Assuntos
Colestenos/sangue , Colestenos/líquido cefalorraquidiano , Ácidos e Sais Biliares/biossíntese , Colestanotriol 26-Mono-Oxigenase/metabolismo , Colestenos/química , Colestenos/normas , Cromatografia Líquida , Humanos , Hidroxilação , Espectrometria de Massas , Paraplegia Espástica Hereditária/sangue , Paraplegia Espástica Hereditária/líquido cefalorraquidiano , Estereoisomerismo , Xantomatose Cerebrotendinosa/sangue , Xantomatose Cerebrotendinosa/líquido cefalorraquidiano
15.
J Clin Lipidol ; 12(1): 240-242, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29195809

RESUMO

Familial chylomicronemia syndrome (FCS) is a rare genetic disorder that is associated with severe hypertriglyceridemia and complications that often include recurrent pancreatitis beginning in childhood. Patients with FCS frequently struggle to maintain normality in their lives as a consequence of the necessity to severely restrict their intake of dietary fat coupled with the constant threat of recurrent pancreatitis. Patients typically face a high level of psychological stress and anxiety in association with reduced measures of quality of life. Routine medical care for affected patients usually does not adequately address the day-to-day struggles that accompany a diagnosis of FCS, resulting in ongoing suffering for many patients. We describe herein the highly beneficial effects of a support group interaction for a patient with FCS.


Assuntos
Adaptação Psicológica , Hiperlipoproteinemia Tipo I/diagnóstico , Ansiedade/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Hiperlipoproteinemia Tipo I/complicações , Hiperlipoproteinemia Tipo I/genética , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Grupos de Autoajuda , Apneia Obstrutiva do Sono/etiologia
16.
J AAPOS ; 21(6): 505-507, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29079218

RESUMO

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease characterized by a broad spectrum of clinical manifestations, including bilateral juvenile cataracts. Untreated CTX leads to progressive permanent neurologic decline and early death. Although symptoms begin in early childhood, diagnosis and replacement therapy with chenodeoxycholic acid is often delayed until adulthood. Frequently bilateral juvenile cataracts present in early childhood which provides ophthalmologists an opportunity to aid in early diagnosis and initiate treatment. We report the case of a child presenting with juvenile bilateral cataracts leading to the diagnosis of CTX. The morphology of cataracts and the effect of systemic treatment on its progression are described.


Assuntos
Catarata/diagnóstico , Diagnóstico Precoce , Xantomatose Cerebrotendinosa/diagnóstico , Astigmatismo/diagnóstico , Extração de Catarata , Catárticos/uso terapêutico , Ácido Quenodesoxicólico/uso terapêutico , Criança , Colestanol/sangue , Humanos , Masculino , Miopia/diagnóstico , Acuidade Visual , Xantomatose Cerebrotendinosa/sangue , Xantomatose Cerebrotendinosa/tratamento farmacológico
17.
Atherosclerosis ; 267: 19-26, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29080546

RESUMO

BACKGROUND AND AIMS: Most familial hypercholesterolemia (FH) patients remain undertreated, and it is unclear what role health disparities may play for FH patients in the US. We sought to describe sex and racial/ethnic disparities in a national registry of US FH patients. METHODS: We analyzed data from 3167 adults enrolled in the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE-FH) registry. Logistic regression was used to evaluate for disparities in LDL-C goals and statin use, with adjustments for covariates including age, cardiovascular risk factors, and statin intolerance. RESULTS: In adjusted analyses, women were less likely than men to achieve treated LDL-C of <100 mg/dL (OR 0.68, 95% CI, 0.57-0.82) or ≥50% reduction from pretreatment LDL-C (OR 0.79, 95% CI, 0.65-0.96). Women were less likely than men to receive statin therapy (OR, 0.60, 95% CI, 0.50-0.73) and less likely to receive a high-intensity statin (OR, 0.60, 95% CI, 0.49-0.72). LDL-C goal achievement also varied by race/ethnicity: compared with whites, Asians and blacks were less likely to achieve LDL-C levels <100 mg/dL (Asians, OR, 0.47, 95% CI, 0.24-0.94; blacks, OR, 0.49, 95% CI, 0.32-0.74) or ≥50% reduction from pretreatment LDL-C (Asians, OR 0.56, 95% CI, 0.32-0.98; blacks, OR 0.62, 95% CI, 0.43-0.90). CONCLUSIONS: In a contemporary US population of FH patients, we identified differences in LDL-C goal attainment and statin usage after stratifying the population by either sex or race/ethnicity. Our findings suggest that health disparities contribute to the undertreatment of US FH patients. Increased efforts are warranted to raise awareness of these disparities.


Assuntos
LDL-Colesterol/sangue , Disparidades nos Níveis de Saúde , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/etnologia , Adulto , Afro-Americanos , Idoso , Americanos Asiáticos , Doenças Cardiovasculares/metabolismo , HDL-Colesterol/metabolismo , Grupos Étnicos , Feminino , Disparidades em Assistência à Saúde , Humanos , Hiperlipoproteinemia Tipo II/sangue , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Razão de Chances , Fenótipo , Estudos Prospectivos , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais
19.
Metab Syndr Relat Disord ; 14(10): 463-467, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27797643

RESUMO

Familial hypercholesterolemia (FH) is a common genetic disorder that can manifest clinically as both the severe homozygous (HoFH) form that often presents in childhood and the commoner heterozygous (HeFH) form that is typically identified in adults. The majority of genetic causes are due to defects in low-density lipoprotein (LDL) receptor synthesis and action. Until recently, it was exceedingly difficult to achieve the goal of a 50% reduction in LDL-cholesterol or LDL-C < 70-100 in these patients. Established therapies include statins, niacin, bile-acid sequestrants, and ezetimibe in various combinations. The recent advent of monoclonal antibodies to PCSK9 (evolocumab and alirocumab) has revolutionized the management of FH and results in a substantial reduction in LDL-C and also reductions in Lp(a). In addition, the previous ushering in of antisense therapy against apoB (mipomersen) and inhibition of microsomal transfer protein (lomitapide) for use in HoFH greatly enhanced our ability to manage refractory hypercholesterolemia in these patients. Hence, the therapeutic landscape for this common disorder has changed dramatically for these patients, with a strong promise for a reduction in cardiovascular events.


Assuntos
Hiperlipoproteinemia Tipo II/terapia , Anticolesterolemiantes/uso terapêutico , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Intervenção Médica Precoce/métodos , Intervenção Médica Precoce/tendências , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/genética , Estilo de Vida , Fatores de Risco , Comportamento de Redução do Risco
20.
J Clin Lipidol ; 10(5): 1223-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27678440

RESUMO

BACKGROUND: In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear. OBJECTIVE: To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry. METHODS: We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: "clinical diagnosis," MEDPED, Simon Broome, DLCN, and other. RESULTS: Most adults enrolled in CASCADE FH (55.0%) received a "clinical diagnosis." The most commonly used formal criteria was Simon-Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a "clinical diagnosis," 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry. CONCLUSIONS: Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.


Assuntos
Hiperlipoproteinemia Tipo II/diagnóstico , Adulto , LDL-Colesterol/sangue , Estudos Transversais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Médicos , Sistema de Registros , Estados Unidos
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